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Endothelin B receptor-mediated increase of cerebral blood flow in experimental pneumococcal meningitis
Abstract:
Study investigates the role of endothelin (ET) receptors in mediating early changes in cerebral blood flow--as measured by laser Doppler flowmetry (CBFLDF)--during experimental pneumococcal meningitis. Meningitis was induced with heat-killed pneumococci and confirmed by a significant increase in CBFLDF (baseline 100%; 225.3 +/- 21.8% after 6 hours; mean +/- SD), intracranial pressure (ICP), brain water content, and white blood cell count in the CSF. Intravenous administration of the selective endothelin B (ETB) receptor antagonist BQ-788 immediately before pneumococcal challenge (but not 4 hours afterward) significantly attenuated these pathophysiologic alterations (e.g., CBFLDF 6 hours after pneumococcal challenge: 116.7 +/- 17.4%). Pretreatment with BQ-123, a selective endothelin A receptor antagonist, had no significant effect on ICP and brain water content, but augmented the increase in CBFLDF and CSF white blood cell count. Since ET is known to trigger the release of nitric oxide (NO) by ETB receptor activation, we examined specific ET-NO interactions in primary rat cerebromicrovascular endothelial cells after stimulation with heat-killed pneumococci. Pneumococci induced a significant increase in both ET and NO concentrations in endothelial cell culture medium. Treatment with phosphoramidon, an inhibitor of the endothelin-converting enzyme, prevented the production of endothelin and markedly reduced NO generation. Our data provide evidence that ET is involved as a mediator in early pneumococcal meningitis in the rat and contributes to the increase in CBFLDF, ICP, brain water content, and CSF pleocytosis, presumably through ETB receptor-mediated NO production.
Insights
Endothelin (ET) receptor B antagonists can reduce early changes in cerebral blood flow and intracranial pressure during experimental pneumococcal meningitis by modulating nitric oxide production.
Area of Science:
- Neuroscience
- Pharmacology
- Infectious Diseases
Background:
- Pneumococcal meningitis causes early changes in cerebral blood flow and intracranial pressure.
- Endothelin (ET) receptors are implicated in cerebrovascular regulation.
- Nitric oxide (NO) plays a role in mediating inflammatory responses in meningitis.
Purpose of the Study:
- To investigate the role of endothelin (ET) receptors in early cerebral blood flow changes during experimental pneumococcal meningitis.
- To explore the interaction between ET and nitric oxide (NO) in this model.
- To evaluate the therapeutic potential of ET receptor antagonists.
Main Methods:
- Induction of meningitis in rats using heat-killed pneumococci.
- Measurement of cerebral blood flow (CBFLDF) using laser Doppler flowmetry.
- Administration of selective endothelin A (ETA) and endothelin B (ETB) receptor antagonists (BQ-123 and BQ-788).
- Assessment of intracranial pressure (ICP), brain water content, and cerebrospinal fluid (CSF) white blood cell count.
- In vitro study of ET-NO interactions in rat cerebromicrovascular endothelial cells.
Main Results:
- Pneumococcal meningitis significantly increased CBFLDF, ICP, brain water content, and CSF white blood cell count.
- ETB receptor antagonist BQ-788 significantly attenuated these pathophysiologic alterations when administered before pneumococcal challenge.
- ETA receptor antagonist BQ-123 had no effect on ICP or brain water content but augmented CBFLDF and CSF pleocytosis.
- Pneumococci increased ET and NO concentrations in endothelial cells; phosphoramidon inhibited ET and NO production.
- ETB receptor activation appears to mediate NO production.
Conclusions:
- Endothelin (ET) is a key mediator in the early stages of experimental pneumococcal meningitis.
- ET contributes to increased cerebral blood flow, intracranial pressure, brain edema, and CSF pleocytosis.
- These effects are likely mediated via ETB receptor activation and subsequent nitric oxide (NO) production.
- ETB receptor antagonists show potential for therapeutic intervention in early pneumococcal meningitis.